Practical Considerations in Managing Hepatorenal Syndrome · Summary 1. Differential diagnosis of AKI in cirrhosis is broad, do not rush to label it HRS 2. If SBP is present, suspicion

Practical Considerations in Managing Hepatorenal Syndrome

Juan Carlos Q. Velez, MDAssociate Professor of Medicine, Ochsner Clinical School / The University of Queensland

Chair, Department of Nephrology, Ochsner Clinic Foundation

2019 Crescent City GI, Endoscopy and Liver Disease Update

New Orleans, LA, September, 2019

@VelezNephHepato

Disclosure of Conflict of Interest

• I have served in an Advisory Board for Mallinckrodt Pharmaceuticals, maker of terlipressin

• I am a member of the Speaker Bureau for Mallinckrodt Pharmaceuticals (corticotropin gel) and for Otsuka Pharmaceuticals (tolvaptan)

Hepatorenal physiology/syndrome (HRS-1)✓ Splanchnic vasodilation, nitric oxide, decrease in SVR

✓ Renal vasoconstriction

✓ Activation of sympathetic nervous and renin-

angiotensin systems

✓ Hepatorenal reflex

✓ Increased sensitivity to vasoconstriction (endotoxin,

endothelin-1, ROS)

✓ Reduction in cortical renal blood flow

✓ Derangement in renal autoregulatory curve

ACS

Cholemic

nephropathy✓ Toxic and pro-

inflammatory tubular

injury from bile

salts, endotoxin,

intraluminal casts

(total bilirubin ~ > 20

mg/dL)

Ischemic ATN✓ Prolonged

prerenal azotemia

✓ Progression from

unresolved HRS-1

Inflammatory

ATI ✓ Endotoxin, toll

receptor

stimulation

PRA

ATI / ATN

Prerenal azotemia (PRA)✓ Decreased effective arterial blood volume

✓ GI losses: lactulose use, GI bleeding, LVP

✓ Renal losses: diuretic use

✓ Other: infections, poor po intake

✓ Cardiorenal: PoPH, high output HF,

cirrhotic cardiomyopathy

HRS-1

Control kidney cortex

Cirrhotic kidney cortex

A

B

Abdominal

compartment

syndrome (ACS)✓ Tense ascites,

intraabdominal

hypertension (bladder

pressure ~ > 20

mmHg)

AGN

AIN

Acute glomerulonephritis

(AGN)✓ HCV-MPGN, IgAN

Acute interstitial

nephritis (AIN)✓ Antibiotics for SBP

(e.g., quinolones)

AKICKD

✓ IgAN, GS

✓ HCV-MPGN

✓ Prior AKIs

Practical Consideration # 1: Differential diagnosis of AKI in cirrhosis is broad

Spontaneous Bacterial

Peritonitis (SBP)

%

25

50

13/27

(48%)

7/27

(27%)

9/27

(33%)

%

25

50HRS-1

83/252

(33%)

Follo A et al(Hepatology 1994)

Hampel H et alAm J Gastro 2001)

Watt K et al(Am J Gastro 2002)

%

25

50 10/23

(43%)

4/23

(17%)

252 SBPs

n = 197

Fernandez J et al(Gastroenterology 2007)

n = 68 n = 23 n = 27

SBP prophylaxis prevents HRS

Practical Consideration # 2

HRS-1 should be suspected in the context of the

presence of a precipitating factor

2015 ICA

HRS-1 Criteria

Angeli P et al(Gut 2015)

Wong F & Angeli P(J Hepatology 2016)

CVP ≥ 8 mmHg?

IVC diameter?


First step should involve

determining if the patient may

respond to intravenous volume

expansion

Velez et al, Am J Nephrol 2019

• Sarcopenia

• High bilirubin interference with Cr

colorimetric assay – artifact

• Daily change in serum Cr is still

useful and valid Control

Cirrhosis

Ebadi M et al(J Gastroenterol 2019)

Practical Consideration # 4:

Absolute serum creatinine (Cr) values

could be misleadingly lower than expected

by degree of AKI

Practical Consideration # 5:

FENa < 1% to diagnose HRSFENa according to

biopsy-proven diagnosis

Alsaad & Wadei et al(World J Hepatol 2016)

n = 88

FENa < 1% and/or Urine Na < 20 mEq/L

is always present but not diagnostic

antibiotics?

10-50 RBCs/hpf?

Foley?

chronic IgA GN?

pyuria?

Angeli P et al(Gut 2015)

Wong F & Angeli P(J Hepatology 2016)

Granular casts, RTECs, WBCs?

UNa < 20 mEq/L ?

IAP < 25 mmHg ?

Low BP “normal” for cirrhotics? What if MAP 90?


Some essential aspects of the HRS-1

phenotype are not included in the

ICA criteria

Hyponatremia? Oliguria?

2015 ICA

HRS-1 Criteria

For liver transplant ineligible patients, why should we treat HRS-1?

Boyer T et al. Terlipressin Study Group

(Liver Transplantation 2011)

3-month transplant-free survival

Responders

41% (7/17)

Non-responders

4% (2/47)

Transplanted: 97% (34/35)n = 99


Even if a patient is not eligible

for liver transplantation, there

is potential benefit in treating

HRS-1

Velez JC & Nietert PJ(Am K Kidney Dis 2011)

Vasoconstrictor Therapy in HRS-1:Raising the Mean Arterial Pressure (MAP)

The main goal of treatment of

HRS-1 with vasoconstrictor

therapy is to raise the MAP

by 15 mmHg or to a target

MAP ~ 85 – 90 mmHg


Vasoconstrictor Therapy in HRS-1

Norepinephrine vs. Terlipressin

% H

RS

Revers

al

43 % 39 %

25

50

75

100

40

50

60

70

80

90

100

0 d15

Mean ∆ MAP(mmHg)

Singh et al.(J Hepatol 2012)

n = 46

% H

RS

Revers

al

50 % 50 %

25

50

75

100

Sharma et al.(Am J Gastroenterol 2008)

n = 40

40

50

60

70

80

90

100

0 4d 8d

Mean ∆ MAP(mmHg)

Vasoconstrictor Therapy in HRS-1:Terlipressin (CONFIRM Trial)

https://clinicaltrials.gov/ct2/show/NCT02770716?term=CONFIRM&cond=Hepatorenal+Syndrome&rank=1

https://www.biospace.com/article/releases/mallinckrodt-announces-positive-top-line-results-from-its-pivotal-phase-3-confirm-trial-of-terlipressin-in-patients-with-hepatorenal-syndrome-type-1-hrs-1-/

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37m

mH

g

Baseline MAP at the time of HRS diagnosis

37 cohorts

Mean: 74.6 mmHg

Median: 76 mmHg

Vasoconstrictor Therapy in HRS-1:Meta-Analysis of 21 Clinical Studies

The MAP at baseline in HRS-1

isn’t necessarily very low,

certainly not less than 65

mmHg. Some patients may

have a MAP up to 80 mmHg

and still benefit from further

rise in MAP


Velez JC & Nietert PJ(Am K Kidney Dis 2011)

Vasoconstrictor Therapy in HRS-1: Raising the MAP

Stadlbauer V et al(Gastroenterology 1999)

Persson P et al(Am J Physiol 1999)

Kelleher S et al(Am J Physiol 1984)

Midodrine / Octreotide is

largely ineffective raising MAP

and revering AKI in HRS-1


Velez JC et al(Nephron 2015)

Acute Kidney Injury during Acute Liver Failure due to Acetaminophen Toxicity is NOT a form of HRS-1

Toxic Acute Tubular Injury

Cultured Proximal Tubular Epithelial Cells: Pyknotic Nuclei

Lorz C et al(JASN 2004)

BONUS: Practical Consideration # 11

4.4 4.1 4.3

1 2 3day

sCr

(mg/dL)3.8

4

4.2 3.93.6

3.12.6

2.4

5 6 7 8 9 10

Biliary tube exchange / IVF (NS)

80MAP

(mmHg)

45 39 36T Bili

(mg/dL)

OLT

1.8

4.2

20

❖ Primary Sclerosing

Cholangitis - ESLD

❖ Baseline sCr 1.1

RFA: worsening jaundice

✓ BP 121/66 mmHg

✓ sNa 138; uNa 22

Case Example 01

70 yo man

4.95.9

7.0

1 2 3day

sCr

(mg/dL)

6.7

4

6.8 – 7.2

5.6

5 6 7 8 9 10

MAP

(mmHg)

3.5

T Bili

(mg/dL)27

❖ Alcoholic, Fatty - ESLD


RFA: ACLF, ETOH intoxication

✓ BP 135/64 mmHg, MAP 88

✓ sNa 132; uNa < 20

Case Example 02

27 yo man

87

LVEF 35%

Leukocytosis37

3.3

4.15.0

1 2 3day

sCr

(mg/dL)

4.5

4

4.8 4.4 3.93.5

3.22.9

5 6 7 8 9 10

IV norepinephrine

7368

8488 8687 88

70

87MAP

(mmHg)

RHC: PAP 55 PCWP 21

IV furosemide

UOP

1 L/d

❖ HCV - ESLD


❖ Pulmonary HTN

RFA: worsening ascites,

evaluation for HCC

✓ BP 92/53 mmHg, MAP 63

✓ sNa 134; uNa < 20

Case Example 03

IV albumin

Midodrine / Octreotide

61 yo man

T Bili

(mg/dL)3.8

❖ ETOH - ESLD


❖ Recently hospitalized

with “sepsis, abdominal

pain, transaminitis”

RFA: elevated serum Cr

✓ BP 92/51 mmHg

✓ sNa 129; uNa 39

✓ Urine leukocytes

Case Example 04

59 yo woman

1.0

4.0

1 2 3day

sCr

(mg/dL)

4

4.3 4.7 4.63.8

2.0

2.9

5 6 7 8 9 10

Clinic lab check,

admitted

Started midodrine +

octreotide

7570

8480

868783

72

85MAP

(mmHg)

T Bili

(mg/dL)1.0

Discharged

from Hosp.

Kidney biopsy: AIN (exposed to Cipro!)

4.3

1.3

Steroids began

AKI stage 1

Initiate Vasoconstrictor Therapy + IV Albumin

Midodrine PO / Octreotide SQ

Not HRS-1 (ATN, AIN, AGN, OU)

Target MAP rise 15 mmHg

or MAP 85 mmHg

Possible HRS-1

AKI stage ≥ 2

Approach to Management of Hepatorenal AKI

>50 RBCs, dysm RBC

>10 WBCs

Cell casts, MBGCs

UPCR >>1.0

UNa > 30

Shock, ↓↓BP, hydronephros

DO NOT Initiate

Vasoconstrictor Therapy for HRS-1

Treat 3-7 days, switch/continue

Midodrine PO / Octreotide SQ

History, physical, IVCd: volume expansion 0 - 3 days: IV albumin

(-) RBCs

(-) WBCs

(-) Prot

UNa < 10

Definite HRS-1

No ResponseNorepinephrine IV or Terlipressin IV

sCr stable or

Volume-unresponsive Hepatorenal AKI

sCr

Target MAP rise 15 mmHg

Repeat if

Recurrence

Response

No Response in 2-3 days

STOP

↑↓ sCr course

urine findings +/-

drug confounders

Abnl RUS or ECHOC

Improbable HRS-1 Probable HRS-1

MAP<80, sNa<135,

oliguria

SpectrumMAP<80, sNa<135, oliguria

Summary

1. Differential diagnosis of AKI in cirrhosis is broad, do not rush to label it HRS

2. If SBP is present, suspicion for HRS increases

3. If history & physical supports it, volume expansion with IV albumin is OK, but watch for volume overload

4. Serum Cr underestimates degree of AKI in cirrhosis, but ∆daily still valid

5. If FENa >1% and/or UNa > 20 mEq/L, think not HRS

6. The ICA HRS criteria are far from perfect, attention to detail is needed

7. In the absence of OLT, successful HRS reversal may improve survival

8. The cornerstone of HRS treatment is pursuance of a rise in MAP by ~15 mmHg or to a goal ≥ 85 mmHg

9. Baseline MAP in HRS could be “normal” (e.g., ~ 70 - 75 mmHg)

10. Midodrine / octreotide is largely ineffective in HRS-1

@VelezNephHepato

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Practical Considerations in Managing Hepatorenal Syndrome · Summary 1. Differential diagnosis of AKI in cirrhosis is broad, do not rush to label it HRS 2. If SBP is present, suspicion